On April 8, 2022 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, reported updated clinical data and new biomarker analyses from its ongoing Phase 2 trial of onvansertib in combination with abiraterone/prednisone in metastatic castrate-resistant prostate cancer (mCRPC) patients (Press release, Cardiff Oncology, APR 8, 2022, View Source [SID1234611704]). The data are featured in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is taking place both virtually and in-person at the Ernest N. Morial Convention Center in New Orleans, Louisiana from April 8-13, 2022.

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"Results from the mCRPC trial demonstrate clinically meaningful disease control rates in patients showing early resistance to abiraterone," said David Einstein, M.D., principal investigator at Beth Israel Deaconess Medical Center. "As the dose density of onvansertib was increased in three consecutive Arms (A, B and C), we observed an increase in disease control rates with both PSA stabilization and radiographic stable disease twelve weeks into treatment and some of these patients have experienced durable stabilization. Pre-clinical data suggest that the synergistic effect is independent of androgen receptor signaling."

The primary efficacy endpoint of the mCRPC trial is disease control rate at 12 weeks (12-week DCR), which is defined by a decline or stabilization of PSA levels (rise of <25% over baseline or less than 2 ng/mL). Each of the trial’s three arms has evaluated a different dosing schedule of onvansertib alongside abiraterone and prednisone administered throughout the respective treatment cycle. Arm A evaluated 24 mg/m2 onvansertib on Days 1-5 of 21-day cycles, Arm B evaluated 18 mg/m2 onvansertib on Days 1-5 of 14-day cycles, and Arm C is evaluating 12 mg/m2 onvansertib on Days 1-14 of 21-day cycles.

"Biomarker correlative studies have revealed significant and positively associated mutations in MTOR, FAT1, PTEN and FOXA1, with tumors harboring these mutations achieving stable disease or a partial response within the initial abiraterone-resistant setting," said Tod Smeal, Ph.D., chief scientific officer of Cardiff Oncology. "In addition, gene expression signatures from patient tumor tissue biopsies correlated with treatment response included those corresponding to the ERG+ and Notch pathways, which are involved in cell-invasion, epithelial-mesenchymal transition and metastasis. We continue to examine these promising biomarker studies with the goal of identifying the genomic alterations most closely associated with response to the combination regimen of onvansertib and abiraterone."

Key data and conclusions from the AACR (Free AACR Whitepaper) poster (cut-off date of February 2, 2022) and ongoing trial include:

Efficacy:

75% (15/20) of evaluable patients in Arm C, which represents the most dose dense treatment schedule, showed disease control by radiographic SD/PR at 12-weeks, compared to 53% (9/17) and 58% (11/19) in the less dose dense Arms A and B, respectively
Biomarker:

Treatment response (SD/PR) was positively associated with mutations in PTEN and MTOR, key genes in the PI3K signaling pathway
Gene signatures correlating with treatment response included those corresponding to the ERG+ and Notch pathways, which are involved in cell-invasion, epithelial-mesenchymal transition and metastasis
Genes related to mitochondrial and immune functions were downregulated in patients achieving SD or a PR compared to those showing progressive disease
Safety:

The treatment regimen of onvansertib in combination with abiraterone/prednisone has been well tolerated
An electronic copy of the poster and corresponding abstract, entitled, Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients, is available to registered attendees of the AACR (Free AACR Whitepaper) annual meeting on the meeting website. The in-person presentation will take place during the "Biomarkers Predictive of Therapeutic Benefit 1" poster session on April 11, 2022, from 9:00 AM – 12:30 PM CT. Following the meeting, the poster will be available on the "Scientific Presentations" section of the Cardiff Oncology website at View Source

On April 8, 2022 Seagen Inc. (Nasdaq: SGEN) reported that a jury in the U.S. District Court for the Eastern District of Texas found that Daiichi Sankyo Co. Ltd. ("Daiichi Sankyo") infringed Seagen’s U.S. Patent No. 10,808,039 by selling in the United States its Enhertu product (trastuzumab deruxtecan; DS-8201) (Press release, Seagen, APR 8, 2022, https://investor.seagen.com/press-releases/news-details/2022/Seagen-Announces-Jury-Award-in-Patent-Infringement-Case-Against-Daiichi-Sankyo/default.aspx [SID1234611703]). Seagen was awarded damages of $41.82 million for past infringement of the patent. In addition, Seagen will request additional royalty payments for future sales of Enhertu in the United States through the life of the patent.

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"We are pleased that the jury recognized the validity of asserted claims of our patent and found that Daiichi Sankyo willfully infringed our proprietary technology without permission," said Clay Siegall, Ph.D., President and Chief Executive Officer, Seagen. "As a pioneer and leader in antibody-drug conjugate (ADC) technology, protecting our intellectual property is essential to our ability to continue developing innovative therapies for cancer patients in need."

In addition to the damages the jury awarded for past infringement, Seagen will request the court to award a royalty on Daiichi Sankyo’s future sales in the United States of Enhertu until patent expiry in November 2024. The court will determine the amount of these payments in a decision Seagen anticipates later this year.

In a related matter, on April 7, 2022, the Patent Trial and Appeal Board of the U.S. Patent and Trademark Office granted a request on rehearing and instituted two post grant review (PGR) proceedings brought against certain claims of U.S. Patent No. 10,808,039. Seagen intends to vigorously defend the patent in the PGRs.

Separately, Seagen is engaged in an arbitration it brought against Daiichi Sankyo over ownership of certain technology used by Daiichi Sankyo in trastuzumab deruxtecan and several other drug candidates. In the arbitration, which remains ongoing, Seagen contends that the linker and other ADC technology used in these compounds are improvements to Seagen’s pioneering ADC technology, the ownership of which is automatically assigned to Seagen under the 2008 collaboration agreement between Daiichi Sankyo and Seagen. A decision in the arbitration case is expected by mid-2022.

On April 8, 2022 Umoja Biopharma, Inc., an oncology company leveraging its proprietary integrated technologies to create next-generation off-the-shelf in vivo(VivoVec) and induced pluripotent stem cell (iPSC) based immunotherapies for the treatment of solid tumors and hematologic malignancies, reported the presentation of data supporting the use of a synthetic cytokine receptor, the Rapamycin Activated Cytokine Receptor (RACR), to derive synthetic innate lymphoid cells, RACR-induced cytotoxic innate lymphoid cells (RACR-iCILs) (Press release, Umoja Biopharma, APR 8, 2022, View Source [SID1234611702]). The data will be presented in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, held from April 8-13, 2022.

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"Some of the current limitations of cell therapies are the need for lymphodepletion, and repetitive lymphodepletion at that, in addition to the challenge of in vivo expansion," said Andy Scharenberg, M.D., co-founder and Chief Executive Officer of Umoja. "Our induced pluripotent stem cell platform seeks to address many of the limitations holding back cell therapy as we know it. By using a synthetic cytokine receptor that can mimic the downstream signaling of the common gamma chain cytokines essential to lymphoid cell differentiation, we are able to create a renewable starting material for scalable manufacturing of synthetic allogeneic chimeric antigen receptor cell products."

On Sunday, April 10th, Samantha O’Hara, Ph.D., Principal Scientist at Umoja Biopharma, will present a poster (Abstract 547) titled "Generation of synthetic cytokine receptor-induced cytotoxic innate lymphocytes (iCILs) from iPSCs as off-the-shelf cancer therapeutics." The data highlights Umoja’s iPSC-based cell therapy platform in which stem cells are engineered ex vivo to express Umoja’s RACR system and a universal adapter-specific TagCAR. The RACR system is intended to be utilized during the manufacturing process where it has the potential to deliver controlled and consistent proliferation and differentiation signals, resulting in the production of a highly pure, induced cytotoxic innate lymphoid cell product. In addition, the RACR system could enable enhanced in vivo engraftment and persistence in the absence of lymphodepleting chemotherapy. The universal adapter-specific TagCAR is designed to enable simultaneous targeting of tumor, tumor stroma, and immunosuppressive cells in the presence of a cocktail of bispecific small molecule adapters, called TumorTags.

On April 8, 2022 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of four preclinical data abstracts focused on its natural killer cell platform and pipeline at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 (Press release, Nkarta, APR 8, 2022, View Source [SID1234611701]).

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"The data we presented at this year’s AACR (Free AACR Whitepaper) meeting highlight the breadth and diversity of our scientific efforts, as we continue to expand our ability to deliver off-the-shelf cell therapies with the potential to disrupt the cancer treatment landscape," said James Trager, PhD, Chief Scientific Officer of Nkarta. "Our research activities are designed to extend the capabilities of NK cells, to lay the groundwork for further pipeline programs – including our pioneering NK+T cell program – and to implement cutting edge translational methods to support our ongoing clinical programs. Our findings reported at AACR (Free AACR Whitepaper) further support exploration of multiply edited CD70 CAR NK cells for clinical application, one focus of our ongoing collaboration with our partners at CRISPR Therapeutics."

Details of the preclinical poster presentations at AACR (Free AACR Whitepaper) follow. Posters are available for download on the Nkarta website (View Source) and on the AACR (Free AACR Whitepaper) e-poster website (View Source).

Presented jointly with CRISPR Therapeutics:

Title: CBLB, CISH and CD70 multiplexed gene knockout with CRISPR/Cas9 enhances cytotoxicity of CD70-CAR NK cells and provides greater resistance to TGF-β for cancer immunotherapy
Session Category:Immunology
Session Title:Preclinical Immunotherapy
Abstract Number:5512

This study illustrates gene editing approaches that enhance the ability of NK cells to target CD70, an antigen highly expressed in a variety of malignant settings, including renal cell carcinoma (RCC) and adenocarcinoma. Editing targets included cytokine inducible SH2-containing protein (CISH) and the E3 ubiquitin ligase CBLB, both negative regulators of NK cell function. Preclinical results showed that a combined editing and engineering strategy to armor primary NK cells via co-expression of the CD70 CAR and a membrane bound form of IL-15 (mbIL-15), together with a triple knockout of CISH, CBLB and CD70 genes using the CRISPR/Cas9 system enhanced anti-tumor activity against renal cell carcinoma (RCC) solid tumor cell lines and provide greater resistance to TGF-β mediated inhibition. These data support the further exploration of CD70/CISH/CBLB triple gene knockout CD70 CAR NK cells for clinical application.

Nkarta presentations:

Title: Surveying surface antigen expression in multiple myeloma preclinical models
Session Category: Tumor Biology
Session Title: Nonclinical Models of Cancer
Abstract Number: 6004

Multiple myeloma (MM) is a progressive hematological cancer with a 5-year survival rate of 53%. Novel therapeutic strategies are being developed to target specific MM surface antigens. Yet, changes in antigen expression through MM progression are poorly understood in the clinic and have not been well characterized in preclinical models. Data presented in this study highlighted antigen expression differences in MM cells when analyzed in mouse tissue compared to in vitro culture. Like the widely variable expression observed between patients, BCMA and CD138 were differentially expressed in the mouse bone marrow between MM models. Commonly targeted antigens in MM also vary kinetically in vivo and can be measured and tracked using flow cytometry. The present findings also support the use of specific cell lines when assessing BCMA, CD38 and CD138-specific immunotherapies or combinatorial approaches to MM treatment.

Title: Development of multiomics approaches to evaluate NKG2D ligand dynamics and anti-tumor immune responses during CAR-NK treatment
Session Category: Clinical Research Excluding Trials
Session Title:Immuno-oncology
Abstract Number:5187

NKX101 is an investigational NK cell therapy engineered to overexpress a chimeric receptor consisting of NKG2D ectodomain, costimulatory signaling motifs, and a membrane-bound form of IL-15. NKX101 is currently under clinical evaluation for treatment of relapsed/refractory acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). To better understand patterns of response to NKX101, we describe the development of several key translational methods, including (i) a single-cell (sc) RNAseq approach to assess gene expression pattern changes in NKX101 and patient cells, (ii) a multiplex IHC panel to monitor NKG2D-ligand expression by cancer cells, and (iii) an ELISA method to detect shed NKG2D-ligand in serum. Employing multiplex IHC and digital image analysis, we found that membrane bound NKG2D-ligands are upregulated in AML and HCC compared to age-matched normal tissue controls. Lastly, using in-house developed ELISAs, we determined that shed NKG2D-ligands can be successfully detected in serum isolated from patients with MDS. Taken together, these assays provide methods for evaluation of NKG2D-ligand dynamics as well as the detection and phenotypic analysis of CAR-NK and immune cell populations in clinical samples.

Title:Immune masking strategies to extend the pharmacokinetics of allogeneic cell therapies
Session Category: Immunology
Session Title:Preclinical Immunotherapy
Abstract Number:5511

Development of immune evasion strategies are underway to improve the pharmacokinetics of allogeneic cell therapies by engineering them to avoid host vs. graft disease, where allogeneic NK and T cells are rapidly targeted by the patient’s own immune system. Hypoimmune strategies are particularly important for the development of allogeneic products containing mixed NK and T cell populations to minimize product cell fratricide. A conventional method for preventing host T rejection of allogenic T cells, is to combine knockout (KO) β-2 microglobulin (β2M) to diminish expression of MHC class I proteins with overexpression of nonclassical MHC class I protein, HLA-E, to evade host NK cell rejection. This study evaluated the effectiveness of HLA-E and other molecules in β2M deficient T cells for inhibiting NK cell cytotoxicity. Concurrently, a high throughput platform was developed to screen NK inhibitory peptides and synthetic ligands to identify novel immune masking strategies for extending allogeneic cell therapy persistence for broad patient populations.

The study showed that the benefit of HLA-E expression in suppressing NK cell cytotoxicity is highly correlated with the expression of NKG2A on the host NK cells. Viral peptides were potent suppressors of NK cell activity, and less dependent on donor NKG2A expression. These data support further exploration of different immune masking strategies in order to extend the pharmacokinetics of allogeneic cell therapies.

On April 8, 2022 Seagen Inc. (Nasdaq: SGEN) reported data from intravesical instillation of enfortumab vedotin (EV) in a non-muscle invasive bladder cancer (NMIBC) preclinical model in addition to preclinical data from SGN-ALPV and SGN-B7H4V, two of its novel antibody-drug conjugates (ADCs) that utilize the company’s proprietary vedotin drug linker technology (Press release, Seagen, APR 8, 2022, View Source [SID1234611700]). These data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, April 8-13, 2022. Seagen and Astellas Pharma Inc. are co-developing enfortumab vedotin under a 50:50 worldwide development and commercialization collaboration.

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"We are encouraged by the preclinical intravesical EV data showing limited systemic exposure and antitumor activity with an encouraging safety profile. These data served as the basis for initiating the ongoing phase 1 trial in patients with NMIBC," said Scott Peterson, Ph.D., Senior Vice President of Research at Seagen. "Additionally, preclinical data presented from SGN-ALPV suggest it may have applications across several tumor types and adds to our broad pipeline of novel ADCs."

Highlights of Seagen Programs Presented at AACR (Free AACR Whitepaper)

Enfortumab Vedotin

Enfortumab vedotin demonstrated antitumor activity in preclinical models of non-muscle invasive bladder cancer (NMIBC). Enfortumab vedotin is directed to Nectin-4, which is highly prevalent in NMIBC. Studies with human bladder cancer cells expressing Nectin-4 showed sustained activity under conditions mimicking intravesical dosing and achieved tumor growth inhibition of 97% when administered in an orthotopic xenograft animal model of NMIBC. Intravesical administration of enfortumab vedotin was well tolerated in a good laboratory practice (GLP) study with minimal local and no systemic toxicities at doses up to six-fold the intravenous maximum tolerated dose.

The antitumor activity and safety profile seen in these preclinical studies support further investigation of intravesical enfortumab vedotin in this patient population, which is now enrolling in a phase 1 trial, EV-104.

SGN-ALPV

SGN-ALPV is a novel ADC designed to target two proteins, ALPP and ALPPL2, to maximize drug delivery. ALPP and ALPPL2 are aberrantly co-expressed in a broad set of solid tumors, including ovarian, endometrial and germ cell cancers. In preclinical studies, SGN-ALPV exhibited robust antitumor activity in cell line and patient-derived xenograft cancer models with both homogenous and heterogeneous expression of placental alkaline phosphatases ALPP and ALPPL2, consistent with robust monomethyl auristatin E (MMAE)-directed cytotoxicity and bystander activity of vedotin ADCs.

Importantly, ALPP and ALPPL2 exhibit a highly restricted normal tissue expression, which may enable a favorable safety profile. Differential expression of ALPP and ALPPL2 in the tumor versus normal tissue, antibody specificity, antitumor activity and tolerability of SGN-ALPV provided a strong rationale for the initiation of the first-in-human phase 1 clinical study currently enrolling patients.

Details of Seagen Presentations at AACR (Free AACR Whitepaper) Annual Meeting 2022:

Abstract Title

Abstract #

Presentation

Presenter

Enfortumab vedotin, a Nectin-4 directed ADC, demonstrates compelling tolerability and anti-tumor activity with intravesical instillation in preclinical models of non-muscle invasive bladder cancer

#1140

Poster session: PO.ET05.02-Preclinical and Clinical Pharmacology, Section 25

April 11

9:00 a.m. – 12:30 p.m. ET

C. Carosino

SGN-B7H4V shows immunomodulatory activity through induction of immunogenic cell death

#1281

Poster session:

PO.CL06.04-Immune Mechanisms Invoked by Other Therapies, Section 32

April 11
9:00 a.m. – 12:30 p.m. ET

E. Gray

SGN-ALPV a novel, investigational vedotin ADC demonstrates highly effective targeting of oncofetal phosphatases ALPP and ALPPL2 in preclinical models

#1766

Poster Session: PO.ET01.04- Antibody-Drug Conjugates, Section 21

April 11

1:30 p.m. – 5:00 p.m. ET

S. Anderson

About Enfortumab Vedotin

Enfortumab vedotin-ejfv (PADCEV) is an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.i,ii Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).

About SGN-ALPV

SGN-ALPV is a novel, investigational vedotin antibody drug conjugate (ADC) designed to bind and internalize the homodimers (ALPP or ALPPL2) or heterodimers (ALPP/ALPPL2-ADC) complex from the surface of tumor cells and release the microtubule-disrupting agent MMAE, inducing cell cycle arrest and apoptosis. SGN-ALPV has demonstrated highly effective targeting of alkaline phosphatases ALPP and ALPPL2 in preclinical models and will be initially evaluated in ovarian and endometrial cancer, non-small cell lung cancer (NSCLC), gastric cancer, cervical cancer, testicular germ cell tumors and ovarian germ cell tumors where ALPP and ALPPL2 are highly prevalent.

About SGN-B7H4V

SGN-B7H4V is a novel, investigational vedotin ADC directed to the T cell checkpoint ligand, B7-H4. B7-H4 expression is limited on normal tissue and overexpressed on a variety of solid malignancies, including breast, ovarian and endometrial tumors. SGN-B7H4V is designed to bind and internalize the B7-H4/ADC complex from the surface of the tumor cells and release the therapeutic payload MMAE, inducing MMAE-mediated direct cytotoxicity, bystander killing and immunogenic cell death, as well as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). SGN-B7H4V demonstrates strong activity in xenograft models, including models with heterogenous B7-H4 expression.